ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.5392A>C (p.Met1798Leu)

dbSNP: rs1555221940
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003656936 SCV001561615 uncertain significance not provided 2023-06-09 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1798 of the POLE protein (p.Met1798Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 1056504). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLE protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002350687 SCV002647004 uncertain significance Hereditary cancer-predisposing syndrome 2024-06-07 criteria provided, single submitter clinical testing The p.M1798L variant (also known as c.5392A>C), located in coding exon 40 of the POLE gene, results from an A to C substitution at nucleotide position 5392. The methionine at codon 1798 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV003656936 SCV005420025 uncertain significance not provided 2024-05-28 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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